The goal of this exploratory proposal is to test the efficacy of adult progenitor cells in amyloid- dependent and amyloid-independent mouse models of Alzheimer's disease (AD). AD poses an increasing burden on society and at present there is no cure or disease modifying treatment. With the continuing failures of anti-amyloid therapies in clinical trials, there is an urgent need for testing alternative strategies aimed at a wider range f targets. Growing evidence suggest that AD is a complex, heterogeneous disorder caused by both amyloid and non-amyloid mechanisms and that neuroinflammation, an invariant feature of AD, may be causally associated with late onset AD. Previous studies in our laboratories have collectively demonstrated: (1) neuroinflammation plays a crucial role in AD pathogenesis; and (2) intravenously administered bone marrow- derived Multi-potent Adult Progenitor Cells (MAPC) exert anti-inflammatory effects and protect rodents from stroke and brain injuries. We propose to leverage novel methodology of intravenous MAPC administration to target inflammation in AD using APPPS1 mice (expressing mutant APP and Presenilin 1) and AICD-Tg mice (expressing APP IntraCellular Domain) as amyloid- and non-amyloid models of AD phenotype, respectively. In Aim 1, we will inject MAPC, once a month for 4 months, prophylactically prior to the appearance of neurological symptoms and test the mice for memory deficits in four different behavioral paradigms. In addition, we will examine the brains for tau phosphorylation, gliosis, cytokine levels, and blood-brain barrier deficits. In the second arm of the study, we will inject MAPC therapeutically once a month for 4 months after the signs of memory deficits become apparent and test mice for the behavioral deficits and brain pathologies described above. The studies in Aim 2 are aimed towards examining the underlying mechanism(s) of intravenously administered MAPC and will test the hypothesis that the effect of MAPC is mediated by downregulation of peripheral immune responses. Spleens will be isolated at the end of the treatment period and splenocytes will be examined to identify activated macrophages, granulocytes, T cells, B cells, etc. In the second arm of the study, we will isolate spleen RNA and perform gene expression analysis to determine whether MAPC treatment blocked the activation of immune gene networks. The proposed studies will demonstrate to what extent adult progenitor cells are effective in preventing AD pathology and rescuing behavioral deficits in both amyloid-dependent and amyloid-independent mechanisms of AD. These studies will also determine whether MAPC are effective therapeutically or need to be used prophylactically. Our studies will examine the potential mechanism(s) underlying the effects of MAPC in AD mouse models and may uncover new molecular drug targets for further exploration.